US2025041303A1PendingUtilityA1
Combination therapy for cancer treatment
Assignee: INSTITUTE FOR CANCER RES D/B/A THE RES INSTITUTE OF FOX CHASE CANCER CENTERPriority: Nov 30, 2021Filed: Nov 29, 2022Published: Feb 6, 2025
Est. expiryNov 30, 2041(~15.3 yrs left)· nominal 20-yr term from priority
Inventors:James S. Duncan
A61K 31/436A61K 31/506A61K 45/06A61K 31/453A61P 35/02A61K 31/519A61K 31/166A61K 31/517A61K 47/55A61P 35/00
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Claims
Abstract
Pharmaceutical compositions comprising: one or more PROTAC therapeutic agents; and one or more kinase inhibitors, one or more ABC transporter inhibitors, or one or more dual ABC transporter/kinase inhibitors, or any combination thereof; and methods of treating cancer in a human by administering: one or more PROTAC therapeutic agents; and one or more kinase inhibitors, one or more ABC transporter inhibitors, or one or more dual ABC transporter/kinase inhibitors, or any combination thereof, are described herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A pharmaceutical composition comprising:
one or more PROTAC therapeutic agents; and one or more kinase inhibitors, one or more ABC transporter inhibitors, or one or more dual ABC transporter/kinase inhibitors, or any combination thereof.
2 . The pharmaceutical composition according to claim 1 , comprising one or more PROTAC therapeutic agents, one or more kinase inhibitors, and one or more ABC transporter inhibitors.
3 . The pharmaceutical composition according to claim 1 , comprising one or more PROTAC therapeutic agents and one or more dual ABC transporter/kinase inhibitors.
4 . The pharmaceutical composition according to any one of claims 1 to 3 , wherein the PROTAC targets the EGFR-KRAS-PI3K-MEK signaling pathway.
5 . The pharmaceutical composition according to claim 4 , wherein the PROTAC targets EGFR, HER2, HER3, PI3K, AKT, KRAS, RAF, MEK, or ERK.
6 . The pharmaceutical composition according to any one of claims 1 to 5 , wherein the kinase inhibitor is an RTK signaling pathway inhibitor.
7 . The pharmaceutical composition according to claim 6 , wherein the RTK signaling pathway inhibitor is an INSR/IGF1R inhibitor, an EGFR/ERBB/HER2/HER3/HER4 inhibitor, an RTK inhibitor, an MERTK inhibitor, an MST1R inhibitor, or an FGFR1 inhibitor, or any combination thereof.
8 . The pharmaceutical composition according to claim 7 , wherein the INSR/IGF1R inhibitor is GSK1904529A, the EGFR/ERBB/HER2/HER3/HER4 inhibitor is lapatinib, the RTK inhibitor is imatinib, the MERTK inhibitor is MRX-2843, the MST1R inhibitor is LY2801653 dihydrochloride, and the FGFR1 inhibitor is PD173074.
9 . The pharmaceutical composition according to any one of claims 1 to 5 , wherein the kinase inhibitor is an MTOR signaling pathway inhibitor.
10 . The pharmaceutical composition according to claim 9 , wherein the MTOR signaling pathway inhibitor is an mTORC1 inhibitor, a PI3K inhibitor, a P70S6K inhibitor, a PI4K2A inhibitor, or a CDK9 inhibitor, or any combination thereof.
11 . The pharmaceutical composition according to claim 10 , wherein the mTORC1 inhibitor is RAD001 or Torin-1, the PI3K inhibitor is GDC-0941, the P70S6K inhibitor is LY2584702, the PI4K2A inhibitor is PI-273, and the CDK9 inhibitor is NVP-2.
12 . The pharmaceutical composition according to any one of claims 1 to 5 , wherein the kinase inhibitor is a CDK7 inhibitor, CK2, AKT1/2, AAK1, FAK1, MEK, and RAF inhibitor.
13 . The pharmaceutical composition according to claim 9 , wherein the MTOR inhibitor is Dactolisib (BEZ235 or NVP-BEZ235), Rapamycin (Sirolimus), Everolimus (RAD001), AZD8055, Temsirolimus (CCI-779 or NSC 683864), PI-103, KU-0063794, Torkinib (PP242), Tacrolimus (FK506), Ridaforolimus (Deforolimus or MK-8669), Sapanisertib (INK 128, MLN0128, or TAK-228), Voxtalisib (SAR245409 or XL765) Analogue, Torin 1, Omipalisib (GSK2126458 or GSK458), OSI-027, PF-04691502, Apitolisib (GDC-0980 or RG7422), GSK1059615, WYE-354, Gedatolisib (PF-05212384 or PKI-587), Torin 2, WYE-125132 (WYE-132), Vistusertib (AZD2014), BGT226 (NVP-BGT226), Palomid 529 (P529), PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, Zotarolimus (ABT-578), LY3023414, CC-115, MHY1485, CZ415, GDC-0084, Voxtalisib (XL765 or SAR245409), 3BDO, Bimiralisib (PQR309), CC-223, or SF2523.
14 . The pharmaceutical composition according to claim 3 , wherein the PROTAC targets the EGFR-KRAS-PI3K-MEK signaling pathway and the dual ABC transporter/kinase inhibitor is lapatinib or RAD001.
15 . The pharmaceutical composition according to claim 3 , wherein the PROTAC targets the EGFR-KRAS-PI3K-MEK signaling pathway and the dual ABC transporter/kinase inhibitor is lapatinib.
16 . The pharmaceutical composition according to claim 14 or claim 15 , wherein the PROTAC targets EGFR, HER2, HER3, PI3K, AKT, KRAS, RAF, MEK, or ERK.
17 . The pharmaceutical composition according to any one of claims 1 to 16 , further comprising one or more KRAS inhibitors and/or one or more autophagy inhibitors.
18 . The pharmaceutical composition according to any one of claims 1 to 17 , wherein a PROTAC therapeutic agent is linked to a kinase inhibitor in the form of a caged molecule.
19 . The pharmaceutical composition according to any one of claims 1 to 17 , wherein a PROTAC therapeutic agent is linked to an ABC transporter inhibitor in the form of a caged molecule.
20 . The pharmaceutical composition according to any one of claims 1 to 17 , wherein a PROTAC therapeutic agent is linked to a dual ABC transporter/kinase inhibitor in the form of a caged molecule.
21 . A method for augmenting the therapeutic effect of a human undergoing cancer treatment with a PROTAC therapeutic agent, the method comprising administering one or more kinase inhibitors, one or more ABC transporter inhibitors, or one or more dual ABC transporter/kinase inhibitors, or any combination thereof, to the human.
22 . The method according to claim 21 , wherein the method comprises administering one or more kinase inhibitors and one or more ABC transporter inhibitors to the human.
23 . The method according to claim 21 , wherein the method comprises administering one or more dual ABC transporter/kinase inhibitors to the human.
24 . The method according to any one of claims 21 to 23 , wherein the PROTAC therapeutic agent targets the EGFR-KRAS-PI3K-MEK signaling pathway.
25 . The method according to claim 24 , wherein the PROTAC therapeutic agent targets EGFR, HER2, HER3, PI3K, AKT, KRAS, RAF, MEK, or ERK.
26 . The method according to any one of claims 21 to 25 , wherein the kinase inhibitor is an RTK signaling pathway inhibitor.
27 . The method according to claim 26 , wherein the RTK signaling pathway inhibitor is an INSR/IGF1R inhibitor, an EGFR/ERBB/HER2/HER3/HER4 inhibitor, an RTK inhibitor, an MERTK inhibitor, an MST1R inhibitor, or an FGFR1 inhibitor, or any combination thereof.
28 . The method according to claim 27 , wherein the INSR/IGF1R inhibitor is GSK1904529A, the EGFR/ERBB/HER2/HER3/HER4 inhibitor is lapatinib, the RTK inhibitor is imatinib, the MERTK inhibitor is MRX-2843, the MST1R inhibitor is LY2801653 dihydrochloride, and the FGFR1 inhibitor is PD173074.
29 . The method according to any one of claims 21 to 25 , wherein the kinase inhibitor is an MTOR signaling pathway inhibitor.
30 . The method according to claim 29 , wherein the MTOR signaling pathway inhibitor is an mTORC1 inhibitor, a PI3K inhibitor, a P70S6K inhibitor, a PI4K2A inhibitor, or a CDK9 inhibitor, or any combination thereof.
31 . The method according to claim 30 , wherein the mTORCT inhibitor is RAD001 or Torin-1, the PI3K inhibitor is GDC-0941, the P70S6K inhibitor is LY2584702, the PI4K2A inhibitor is PI-273, and the CDK9 inhibitor is NVP-2.
32 . The method according to any one of claims 21 to 25 , wherein the kinase inhibitor is a CDK7 inhibitor, CK2, AKT1/2, AAK1, FAK1, MEK, and RAF inhibitor.
33 . The method according to claim 29 , wherein the MTOR inhibitor is Dactolisib (BEZ235 or NVP-BEZ235), Rapamycin (Sirolimus), Everolimus (RAD001), AZD8055, Temsirolimus (CCI-779 or NSC 683864), PI-103, KU-0063794, Torkinib (PP242), Tacrolimus (FK506), Ridaforolimus (Deforolimus or MK-8669), Sapanisertib (INK 128, MLN0128, or TAK-228), Voxtalisib (SAR245409 or XL765) Analogue, Torin 1, Omipalisib (GSK2126458 or GSK458), OSI-027, PF-04691502, Apitolisib (GDC-0980 or RG7422), GSK1059615, WYE-354, Gedatolisib (PF-05212384 or PKI-587), Torin 2, WYE-125132 (WYE-132), Vistusertib (AZD2014), BGT226 (NVP-BGT226), Palomid 529 (P529), PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, Zotarolimus (ABT-578), LY3023414, CC-115, MHY1485, CZ415, GDC-0084, Voxtalisib (XL765 or SAR245409), 3BDO, Bimiralisib (PQR309), CC-223, or SF2523.
34 . The method according to claim 23 , wherein the PROTAC targets the EGFR-KRAS-PI3K-MEK signaling pathway and the dual ABC transporter/kinase inhibitor is lapatinib or RAD001.
35 . The method according to claim 23 , wherein the PROTAC targets the EGFR-KRAS-PI3K-MEK signaling pathway and the dual ABC transporter/kinase inhibitor is lapatinib.
36 . The method according to claim 34 or claim 35 , wherein the PROTAC targets EGFR, HER2, HER3, PI3K, AKT, KRAS, RAF, MEK, or ERK.
37 . The method according to any one of claims 21 to 36 , further comprising one or more KRAS inhibitors and/or one or more autophagy inhibitors.
38 . The method according to any one of claims 21 to 37 , wherein the amount of the PROTAC therapeutic agent administered to the human undergoing cancer treatment and receiving administration of one or more kinase inhibitors, one or more ABC transporter inhibitors, or one or more dual ABC transporter/kinase inhibitors, or any combination thereof, is reduced compared to the amount of the PROTAC therapeutic agent administered to a human undergoing cancer treatment in the absence of receiving administration of one or more kinase inhibitors, one or more ABC transporter inhibitors, or one or more dual ABC transporter/kinase inhibitors, or any combination thereof.
39 . The method according to any one of claims 21 to 38 , wherein the cancer is acute myeloid leukemia, acute monocytic leukemia, prostatic adenocarcinoma, ovarian carcinoma, or epithelial ovarian cancer.
40 . The method according to claim 39 , wherein the epithelial ovarian cancer is High-Grade Serous Ovarian Carcinoma (HGSOC).
41 . The method according to any one of claims 21 to 38 , wherein the cancer is a KRAS cancer, PIK3CA cancer, or PTEN cancer.
42 . A method of treating cancer in a human in need thereof, the method comprising administering to the human:
one or more PROTAC therapeutic agents; and one or more kinase inhibitors, one or more ABC transporter inhibitors, or one or more dual ABC transporter/kinase inhibitors, or any combination thereof.
43 . The method according to claim 42 , wherein the human is administered one or more PROTAC therapeutic agents, one or more kinase inhibitors, and one or more ABC transporter inhibitors.
44 . The method according to claim 42 , wherein the human is administered one or more PROTAC therapeutic agents and one or more dual ABC transporter/kinase inhibitors.
45 . The method according to any one of claims 42 to 44 , wherein the PROTAC targets the EGFR-KRAS-PI3K-MEK signaling pathway.
46 . The method according to claim 45 , wherein the PROTAC targets EGFR, HER2, HER3, PI3K, AKT, KRAS, RAF, MEK, or ERK.
47 . The method according to any one of claims 42 to 46 , wherein the kinase inhibitor is an RTK signaling pathway inhibitor.
48 . The method according to claim 47 , wherein the RTK signaling pathway inhibitor is an INSR/IGF1R inhibitor, an EGFR/ERBB/HER2/HER3/HER4 inhibitor, an RTK inhibitor, an MERTK inhibitor, an MST1R inhibitor, or an FGFR1 inhibitor, or any combination thereof.
49 . The method according to claim 48 , wherein the INSR/IGF1R inhibitor is GSK1904529A, the EGFR/ERBB/HER2/HER3/HER4 inhibitor is lapatinib, the RTK inhibitor is imatinib, the MERTK inhibitor is MRX-2843, the MST1R inhibitor is LY2801653 dihydrochloride, and the FGFR1 inhibitor is PD173074.
50 . The method according to any one of claims 42 to 46 , wherein the kinase inhibitor is an MTOR signaling pathway inhibitor.
51 . The method according to claim 50 , wherein the MTOR signaling pathway inhibitor is an mTORC1 inhibitor, a P13K inhibitor, a P70S6K inhibitor, a PI4K2A inhibitor, or a CDK9 inhibitor, or any combination thereof.
52 . The method according to claim 51 , wherein the mTORC1 inhibitor is RAD001 or Torin-1, the PI3K inhibitor is GDC-0941, the P70S6K inhibitor is LY2584702, the PI4K2A inhibitor is PI-273, and the CDK9 inhibitor is NVP-2.
53 . The method according to any one of claims 42 to 46 , wherein the kinase inhibitor is a CDK7 inhibitor, CK2, AKT1/2, AAK1, FAK1, MEK, and RAF inhibitor.
54 . The method according to claim 50 , wherein the MTOR inhibitor is Dactolisib (BEZ235 or NVP-BEZ235), Rapamycin (Sirolimus), Everolimus (RAD001), AZD8055, Temsirolimus (CCI-779 or NSC 683864), PI-103, KU-0063794, Torkinib (PP242), Tacrolimus (FK506), Ridaforolimus (Deforolimus or MK-8669), Sapanisertib (INK 128, MLN0128, or TAK-228), Voxtalisib (SAR245409 or XL765) Analogue, Torin 1, Omipalisib (GSK2126458 or GSK458), OSI-027, PF-04691502, Apitolisib (GDC-0980 or RG7422), GSK1059615, WYE-354, Gedatolisib (PF-05212384 or PKI-587), Torin 2, WYE-125132 (WYE-132), Vistusertib (AZD2014), BGT226 (NVP-BGT226), Palomid 529 (P529), PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, Zotarolimus (ABT-578), LY3023414, CC-115, MHY1485, CZ415, GDC-0084, Voxtalisib (XL765 or SAR245409), 3BDO, Bimiralisib (PQR309), CC-223, or SF2523.
55 . The method according to claim 44 , wherein the PROTAC targets the EGFR-KRAS-PI3K-MEK signaling pathway and the dual ABC transporter/kinase inhibitor is lapatinib or RAD001.
56 . The method according to claim 44 , wherein the PROTAC targets the EGFR-KRAS-PI3K-MEK signaling pathway and the dual ABC transporter/kinase inhibitor is lapatinib.
57 . The method according to claim 55 or claim 56 , wherein the PROTAC targets EGFR, HER2, HER3, PI3K, AKT, KRAS, RAF, MEK, or ERK.
58 . The method according to any one of claims 42 to 57 , further comprising administering one or more KRAS inhibitors and/or one or more autophagy inhibitors to the human.
59 . The method according to any one of claims 42 to 58 , wherein the amount of the PROTAC therapeutic agent administered to the human receiving administration of one or more kinase inhibitors, one or more ABC transporter inhibitors, or one or more dual ABC transporter/kinase inhibitors, or any combination thereof, is reduced compared to the amount of the PROTAC therapeutic agent administered to a human undergoing cancer treatment in the absence of receiving administration of one or more kinase inhibitors, one or more ABC transporter inhibitors, or one or more dual ABC transporter/kinase inhibitors, or any combination thereof.
60 . The method according to any one of claims 42 to 59 , wherein the cancer is acute myeloid leukemia, acute monocytic leukemia, prostatic adenocarcinoma, ovarian carcinoma, or epithelial ovarian cancer.
61 . The method according to claim 60 , wherein the epithelial ovarian cancer is High-Grade Serous Ovarian Carcinoma (HGSOC).
62 . The method according to any one of claims 42 to 59 , wherein the cancer is a KRAS cancer, PIK3CA cancer, or PTEN cancer.
63 . The method according to any one of claims 42 to 62 , wherein MDR1 is overexpressed in the human.
64 . The method according to any one of claims 42 to 63 , wherein a PROTAC therapeutic agent is linked to a kinase inhibitor in the form of a caged molecule.
65 . The method according to any one of claims 42 to 63 , wherein a PROTAC therapeutic agent is linked to an ABC transporter inhibitor in the form of a caged molecule.
66 . The method according to any one of claims 42 to 63 , wherein a PROTAC therapeutic agent is linked to a dual ABC transporter/kinase inhibitor in the form of a caged molecule.Join the waitlist — get patent alerts
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